EP0703786A1 - Utilisation de nona- et decapeptides pour la fabrication d'un medicament contre le sida - Google Patents

Utilisation de nona- et decapeptides pour la fabrication d'un medicament contre le sida

Info

Publication number
EP0703786A1
EP0703786A1 EP94913518A EP94913518A EP0703786A1 EP 0703786 A1 EP0703786 A1 EP 0703786A1 EP 94913518 A EP94913518 A EP 94913518A EP 94913518 A EP94913518 A EP 94913518A EP 0703786 A1 EP0703786 A1 EP 0703786A1
Authority
EP
European Patent Office
Prior art keywords
phe
formula
ala
pal
peptld
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP94913518A
Other languages
German (de)
English (en)
Other versions
EP0703786B1 (fr
Inventor
Jürgen Engel
Bernhard Kutscher
Michael Bernd
Ulf Niemeyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BLITZ F02-570 GmbH
Aeterna Zentaris GmbH
Original Assignee
Asta Medica GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asta Medica GmbH filed Critical Asta Medica GmbH
Publication of EP0703786A1 publication Critical patent/EP0703786A1/fr
Application granted granted Critical
Publication of EP0703786B1 publication Critical patent/EP0703786B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A61K38/105—Bombesin; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/13—Luteinizing hormone-releasing hormone; related peptides

Definitions

  • EP-A 493 378 describes the use of 2 '-3 * -Dedeoxyguanosl n or of mono- or Tr1 phosphates of 2' -3 '-Dedec * : yguanos1 n for the same purpose.
  • the invention relates to the production of a medicament on the basis of pepteal LHRH-antagon1 s and Bo bes1 n-anagon1 s.
  • the compounds are not very toxic even at the highest dosage used.
  • amino acid sequence of the LHRH is:
  • R can have the meanings (C j -C 4 ) acyl or (C 1 -C 10 ) alkyl.
  • Sugar can have the meanings glucose, galactose, allose, old rose, mannose, gulose, idose or talose
  • Bombesln has the following amino acid sequence:
  • Bombesln p-Gl u-Gl n-Arg-Leu-Gly-Asn 6 -Gl n -Trp 8 -Al a 9 -
  • the Bombesi n-anal oge Peptld according to Formula X has the following structure:
  • Welter can be used to treat A1ds bombesin n-antagonists according to the general formula XI:
  • Q means - NH 2 or - OQ 1
  • Q 1 is hydrogen, (C 1 -C 10) -alkyl, phenyl or phenyl which has been substituted once or several times by alkyl groups having 7-10 carbon atoms,
  • X means: hydrogen or a simple blending to the radical A 2 , the acyl radical of an organic acid with 1-6 carbon atoms or a group R 1 -C-
  • R 1 can have the meanings given above in Q 1 or
  • R 2 and R 3 may be the same or different and may be hydrogen or methyl
  • R 2 may be an alkyl group having 1-10 carbon atoms, a phenyl group, one by one or more alkyl groups having 1-10 carbon atoms substituted phenyl group, a phenyl group substituted by one or more halogen atoms, for example fluorine, chlorine, bromine or iodine.
  • a 1 means:
  • X represents an acyl group, an alkyl group (CJ-CJ Q ) or a simple bling and
  • R 5 and R 6 can be identical or different and R 5 is hydrogen, C 1 -C 3 alkyl or phenyl,
  • R 6 is hydrogen or C 1 -C 3 alkyl or
  • -NH-C-NH 2 mean II 0 or -NH-C-NR 8 R g 0 and [-3 is a simple blinding which is the
  • Carboxyl group connects with the ⁇ -Am1 nogroup when X is a simple blinding means Nal, Pal, Tp1, Trp, MeTrp, Trp (For) or
  • Benzene ring is substituted by one or more members from the group halogen, N0 2 , NH 2 , OH, methyl, ethyl or C 1 -C 3 alkoxy, where halogen
  • Pal means a reduced isosteres of Leu or
  • Phe Leu, Met, Phe, Tp1 or substituted
  • Tr1 f1 uacacetate, acetate, sulfate, phosphate, mesylate or tosylate.
  • Dpa means 2, 3-D1 aminoproplonic acid
  • Nal means 3- (2-aphyl) -al an1 n
  • Th1 means ⁇ -2'-Th ; ylalanln,
  • Tp1 means 2, 3, 4, 9- "i etrahydro-lH-pyr1 do-
  • N1c N1cot1noyl
  • Mop means 4- (Morpol 1 nomethyl) -phenyl al an1 n
  • Formula III [Ac-DNal (2) 1 , D-Phe (pCl) 2 , D-Pal (3) 3 , D-C1t 6 , Nva 7 , D-Ala 1 °] -LHRH
  • Formula IV [Ac-DNal (2) 1 , D-Phe (pCl) 2 , D-Trp 3 , D-C1t 6 , D-Ala 10 L-LHRH
  • Formula V [Ac-DNal (2) 1 , D-Phe (pCl) 2 , D-Pal (3) 3 , D-C1t 6 , D-Ala 10 l-LHRH
  • Formula VI [Ac-DNal (2) 1 , D-Phe (pCl) 2 , D-Pal (3) 3 , D-HC1 6 , D-Ala 10 ] -LHRH
  • Formula VII [Ac-DNal (2) 1 , D-Phe (pCl) 2 , D-Pal 3 , D-C1t 6 , t-Leu 7 , D-Ala 10 ] -LHRH
  • Formula VIII [Ac-DNal (2) ⁇ , D-Phe (pCl) 2 , D-Pal (3) 3 , D-C1t 6 , Ala 9 , D-Ala 1 °] -LHRH
  • the 011 gopeptides according to the invention are synthesized according to conventional methods known from the literature. A summary description of the methods that come into question can be found, for example, in M. Bodanszky, Prlndples of Peptides Synthesls, Springer-Verlag, Berlin, Heidelberg, New York 1984.
  • the syntheses of the peptides according to formulas II-VIII arrive at methyl-benzhydryl am1 n resin (hydrochloride or 1-d form) from Advanced Chem. Tech / Lou1 svl 11 e (Kentucky), USA, each of which is before blinding of the C-terminal Boc-D-Al an1 ns by I0% 1ges tr ⁇ ethylamine in dichloromethane (V / V) 1n the free base was transferred.
  • Residues of free amino acids were blocked by acetylation in a five-fold excess of acetylmidazole in dichloromethane.
  • the sequence of the reaction steps of building the Pept1 on the resin is shown in the block diagram.
  • the respective end product of the solid phase synthesis was dried in vacuo and treated in SOOfold excess of HF / An1sol 10: 1 (v / v) for 45 to 60 minutes at 0 ° C.
  • mobile phase B 300 ml water (demineralized water, ultrapure) + 700 ml acetone1tr1l
  • the invention relates to a method for producing a medicament for the treatment of total infections, preferably for the treatment of A1ds.
  • New peptides and their synthesis which can be used for antiral therapy, are described more often.
  • the peptides are not very toxic even at the highest dosage used.
  • the EC 0 values in the NCI test in the peptides examined are between 5.9 x 10 ⁇ 7 mol / L1ter and 2.0 x 10 "* 5 mol / L1ter.
  • the reference compound AZT (Az1 dothyml d1 n) had an EC50 value of 3.10 x 10 ⁇ 9 mol / l.
  • the therapeutic index (TI 50 IC50 / EC50) is then greater than 7.30.
  • the method is suitable for finding active substances which are effective in all phases of the V1 soot cycle.
  • the test pr1nz1p is based on the killing of the T4 lymphocytes by the HIV-V1rus. Small amounts of HIV-V1rus are added to the cell cultures. At least two complete reproductive cycles are required to kill the T4 lymphocytes and to evaluate the results. Active substances that react with V1r1onen (v1 russus-like particles), cells or with products of the viral genes in order to change with vral activities and thus block the multiplication of the viruses will protect the cells from death and from lysis.
  • test system In order to be able to examine a large number of cells infected with viruses, the test system is automated. However, compounds which degenerate, denature or which are rapidly metabolized for 1 s1 cannot be reliably detected with the test arrangement.
  • AZT Az1 dothyml d1 n
  • DDC serve as a positive control for the test.
  • T4 lymphocytes (CEM - Zelll1n1e) are mixed with virus in a virus: cell ratio of approx. 1: 0.05 1n M1 crot1 terpl atten.
  • the substance to be tested is dissolved in D1 methyl sul fox1 d (DMSO) and diluted 1m in a ratio of 1: 200 (weight 1e). Further dilutions are carried out in half a step with DMSO and then applied to both infected and non-infected cell cultures.
  • DMSO D1 methyl sul fox1 d
  • the cultures are incubated for 6-7 days at 37 ° C in a 5% CO 2 atmosphere. 4.
  • the tetrazole 1 micron salt xTT is added to the cell cultures and the cell cultures are incubated to allow the formazan color reaction to proceed by surviving cells by coupling with phenazl nmethosulfonate (PMS).
  • PMS phenazl nmethosulfonate
  • the individual cell cultures are analyzed spectrophotometrically and examined microscopically for surviving cells in order to confirm the protective effect.
  • Treated v1 russian nf1 cells are compared with treated, non-infected cells. Further comparisons (untreated, infected cells and untreated, uninfected cells, drug-containing cells, cell-free wells) are carried out on the same plate.
  • the activity of the tested compound is best1 mt.
  • the peptides according to the invention are therefore suitable for the production of medicaments, for the control of A1ds and for the control of diseases which are associated with the infection with the immunodeficiency virus (A1ds related compl ex, ARC).
  • the dosage of the drug according to the invention is between 0.01 mg and 10 mg with daily administration.
  • Example 1 The dosage of the drug according to the invention is between 0.01 mg and 10 mg with daily administration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Reproductive Health (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP94913518A 1993-06-18 1994-04-02 Utilisation de nona- et decapeptides pour la fabrication d'un medicament contre le sida Expired - Lifetime EP0703786B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4320201 1993-06-18
DE4320201A DE4320201A1 (de) 1993-06-18 1993-06-18 Verwendung von Cetrorelix und weiteren Nona- und Dekapeptiden zur Herstellung eines Arzneimittels zur Bekämpfung von Aids und zur Wachstumsstimulation
PCT/EP1994/001037 WO1995000168A1 (fr) 1993-06-18 1994-04-02 Utilisation de nona- et decapeptides pour la fabrication d'un medicament contre le sida

Publications (2)

Publication Number Publication Date
EP0703786A1 true EP0703786A1 (fr) 1996-04-03
EP0703786B1 EP0703786B1 (fr) 2002-02-13

Family

ID=6490614

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94913518A Expired - Lifetime EP0703786B1 (fr) 1993-06-18 1994-04-02 Utilisation de nona- et decapeptides pour la fabrication d'un medicament contre le sida

Country Status (24)

Country Link
US (1) US5985834A (fr)
EP (1) EP0703786B1 (fr)
JP (1) JPH08511784A (fr)
KR (1) KR100352541B1 (fr)
CN (1) CN1136915C (fr)
AT (1) ATE213164T1 (fr)
AU (1) AU688315B2 (fr)
BR (1) BR9406893A (fr)
CZ (1) CZ285997B6 (fr)
DE (2) DE4320201A1 (fr)
DK (1) DK0703786T3 (fr)
ES (1) ES2172533T3 (fr)
FI (1) FI113008B (fr)
HU (1) HUT73673A (fr)
IL (1) IL110045A (fr)
NO (1) NO320945B1 (fr)
PL (1) PL175580B1 (fr)
PT (1) PT703786E (fr)
RU (1) RU2154492C2 (fr)
SG (1) SG52240A1 (fr)
TW (1) TW370532B (fr)
UA (1) UA41938C2 (fr)
WO (1) WO1995000168A1 (fr)
ZA (1) ZA944347B (fr)

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US5843901A (en) * 1995-06-07 1998-12-01 Advanced Research & Technology Institute LHRH antagonist peptides
US5916582A (en) * 1996-07-03 1999-06-29 Alza Corporation Aqueous formulations of peptides
US5932547A (en) * 1996-07-03 1999-08-03 Alza Corporation Non-aqueous polar aprotic peptide formulations
US5981489A (en) * 1996-07-18 1999-11-09 Alza Corporation Non-aqueous protic peptide formulations
DE19728737C1 (de) * 1997-07-04 1999-02-11 Johannes Christian Groeninghen Verfahren zur Erkennung und Bestimmung von GnRH-Rezeptoren und die Verwendung von GnRH-Agonisten und GnRH-Antagonisten zur Behandlung eines Tumors ausgehend vom Hirn und/oder Nervensystem und/oder den Hirnhäuten
US8962558B2 (en) 1997-07-04 2015-02-24 Johannes C. van Groeninghen Methods for reducing GnRH-positive tumor cell proliferation using the GnRH antagonist IN3
EP1268522B1 (fr) * 2000-03-14 2008-09-17 AEterna Zentaris GmbH Nouveaux antagonistes de la lhrh, sa production et son utilisation comme medicament
DE10137174A1 (de) * 2001-07-31 2003-02-13 Zentaris Ag Verwendung von LHRH-Antagonisten in nichtkastrierenden Dosen zur Verbesserung der T-Zellen-vermittelten Immunität
US20040138138A1 (en) * 2001-08-02 2004-07-15 Jurgen Engel Use of LHRH-antagonists in doses that do not cause castration for the improvement of T-cell mediated immunity
IL147138A0 (en) * 2001-12-17 2002-08-14 Yeda Res & Dev Methods of and pharmaceutical compositions for modulating cell adhesion, migration and extravasation
GB0130219D0 (en) * 2001-12-18 2002-02-06 Pfizer Ltd Compounds for the treatment of sexual dysfunction
US7250514B1 (en) * 2002-10-21 2007-07-31 Takeda San Diego, Inc. Histone deacetylase inhibitors
CA2726247C (fr) * 2008-05-29 2018-06-26 Isr Immune System Regulation Ab Procede et moyens de traitement d'une maladie virale, en particulier le vih/sida
US20110229877A1 (en) 2008-07-07 2011-09-22 Oxford Nanopore Technologies Limited Enzyme-pore constructs
CA2730068A1 (fr) 2008-07-07 2010-01-14 Oxford Nanopore Technologies Limited Pore detecteur de bases
GB0820927D0 (en) 2008-11-14 2008-12-24 Isis Innovation Method
CA2750879C (fr) 2009-01-30 2018-05-22 Oxford Nanopore Technologies Limited Adaptateurs pour des constructions d'acide nucleique dans le sequencage de sequences transmembranaires
WO2010086603A1 (fr) * 2009-01-30 2010-08-05 Oxford Nanopore Technologies Limited Enzyme mutante
GB0905140D0 (en) 2009-03-25 2009-05-06 Isis Innovation Method
CA2826374C (fr) 2011-02-11 2024-01-23 Oxford Nanopore Technologies Limited Pores mutants
KR20140050067A (ko) 2011-07-25 2014-04-28 옥스포드 나노포어 테크놀로지즈 리미티드 막횡단 포어를 사용한 이중 가닥 폴리뉴클레오티드 서열분석을 위한 헤어핀 루프 방법
CA2869546C (fr) 2012-04-10 2020-07-21 Oxford Nanopore Technologies Limited Pores formes de lysenine mutante
EP2875154B1 (fr) 2012-07-19 2017-08-23 Oxford Nanopore Technologies Limited Procédé SSB pour caractériser un acide nucléique
KR102168813B1 (ko) 2013-03-08 2020-10-22 옥스포드 나노포어 테크놀로지즈 리미티드 효소 정지 방법
GB201314695D0 (en) 2013-08-16 2013-10-02 Oxford Nanopore Tech Ltd Method
GB201313477D0 (en) 2013-07-29 2013-09-11 Univ Leuven Kath Nanopore biosensors for detection of proteins and nucleic acids
GB201403096D0 (en) 2014-02-21 2014-04-09 Oxford Nanopore Tech Ltd Sample preparation method
US10167503B2 (en) 2014-05-02 2019-01-01 Oxford Nanopore Technologies Ltd. Mutant pores
CN117164683A (zh) 2014-09-01 2023-12-05 弗拉芒区生物技术研究所 突变csgg孔
EP3204511B1 (fr) 2014-10-07 2021-07-28 Oxford Nanopore Technologies Limited Pores mutants
GB201418159D0 (en) 2014-10-14 2014-11-26 Oxford Nanopore Tech Ltd Method
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GB201609220D0 (en) 2016-05-25 2016-07-06 Oxford Nanopore Tech Ltd Method
GB201807793D0 (en) 2018-05-14 2018-06-27 Oxford Nanopore Tech Ltd Method

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Also Published As

Publication number Publication date
AU688315B2 (en) 1998-03-12
NO320945B1 (no) 2006-02-20
DK0703786T3 (da) 2002-05-27
HU9503605D0 (en) 1996-02-28
DE59410052D1 (de) 2002-03-21
EP0703786B1 (fr) 2002-02-13
PT703786E (pt) 2002-07-31
IL110045A (en) 2000-06-01
ES2172533T3 (es) 2002-10-01
US5985834A (en) 1999-11-16
FI956014A (fi) 1995-12-14
KR960703015A (ko) 1996-06-19
NO954996D0 (no) 1995-12-08
CN1125400A (zh) 1996-06-26
TW370532B (en) 1999-09-21
FI113008B (fi) 2004-02-27
KR100352541B1 (ko) 2002-12-26
CZ285997B6 (cs) 1999-12-15
CZ308995A3 (en) 1996-03-13
ZA944347B (en) 1995-02-15
UA41938C2 (uk) 2001-10-15
IL110045A0 (en) 1994-10-07
FI956014A0 (fi) 1995-12-14
RU2154492C2 (ru) 2000-08-20
PL312219A1 (en) 1996-04-01
JPH08511784A (ja) 1996-12-10
CN1136915C (zh) 2004-02-04
NO954996L (no) 1995-12-08
BR9406893A (pt) 1996-09-10
DE4320201A1 (de) 1995-01-12
ATE213164T1 (de) 2002-02-15
AU6564794A (en) 1995-01-17
PL175580B1 (pl) 1999-01-29
HUT73673A (en) 1996-09-30
SG52240A1 (en) 1998-09-28
WO1995000168A1 (fr) 1995-01-05

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